Discovery of inhibitors against SARS-CoV-2 main protease using fragment-based drug design.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of coronavirus disease 2019 (COVID-19), in which the main protease (Mpro) plays an important role in the virus's life cycle. In this work, two representative peptide inhibitors (11a and PF-07321332) were selected, and their interaction mechanisms of non-covalently bound with Mpro were firstly investigated by means of molecular dynamical simulation. Then, using the fragment-based drug design method, some fragments from the existing SARS-CoV and SARS-CoV-2 inhibitors were selected to replace the original P2 and P3 fragments, resulting in some new molecules. Among them, two molecules (O-74 and N-98) were confirmed by molecular docking and molecular dynamics simulation, and ADMET properties prediction was employed for further verification. The results shown that they presented excellent activity and physicochemical properties, and had the potential to be new inhibitors for SARS-CoV-2 main protease.

Biological effect of black phosphorus nanosheets on the interaction between SARS-CoV-2 S protein and ACE2.

The binding of the spike glycoprotein (S protein) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to angiotensin-converting enzyme 2 (ACE2) is the main pathway that leads to serious coronavirus disease 2019 (COVID-19) infection. In the biomedical applications of various nanomaterials, black phosphorus nanosheets (BP) have been receiving increasing attention owing to their excellent characteristics. In this study, the biological effect of BP on the interaction between the S protein and ACE2 was investigated by molecular dynamics simulations. The results indicated that the ACE2 could be quickly and stably adsorbed on the BP surface by non-specific binding and retain its structural integrity. Compared with the case without BP, the interaction of the S protein bound to ACE2 adsorbed on the BP surface was greatly weakened, including hydrogen bonds, salt bridges, and van der Waals forces. This study not only reveals that BP could effectively obstruct the binding of S protein and ACE2, which may provide a potential and reasonable drug carrier to further enhance the curative effect of inhibitors against SARS-CoV-2 infection, but also presents a novel interference mechanism for protein-protein interactions caused by nanomaterials.